Enantioselective Synthesis, DFT Calculations, and Preliminary Antineoplastic Activity of Dibenzo 1-Azaspiro[4.5]decanes on Drug-Resistant Leukemias

Mendes, J.A. ; Merino, P. (Universidad de Zaragoza) ; Soler, T. ; Salustiano, E.J. ; Costa, P.R.R. ; Yus, M. ; Foubelo, F. ; Buarque, C.D.

Resumen: The addition of 2-bromobenzylmagnesium bromide to chiral N- tert-butanesulfinyl imines derived from tetralone-type ketones proceeds with high levels of diastereocontrol. The resulting sulfinamide derivatives were transformed into dibenzoazaspiro compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. Similar results have been obtained considering either diethyl ether or toluene as a solvent, in both cases in an excellent agreement with experimental findings. NCI topological calculations have also been used to evidence crucial noncovalent interactions. In addition, the azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar range. Notably, both the halogen-substituted ( R)- and ( S)-8g and -8h as well as ( R)-8j were at least two times more effective on a multidrug-resistant derivative than on the parental cell line, exerting a collateral sensitivity effect.

Idioma: Inglés

DOI: 10.1021/acs.joc.8b03203

Año: 2019

Publicado en: JOURNAL OF ORGANIC CHEMISTRY 84, 4 (2019), 2219-2233
ISSN: 0022-3263

Factor impacto JCR: 4.335 (2019)

Categ. JCR: CHEMISTRY, ORGANIC rank: 9 / 57 = 0.158 (2019) - Q1 - T1

Factor impacto SCIMAGO: 1.349 - Organic Chemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2014-51912-REDC
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2014-53695-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-76155-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-81797-REDC
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2017-85093-P

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)